Background <p>Opioids are frequently used in general anesthesia but may delay recovery owing to adverse effects, which include respiratory depression, postoperative nausea and vomiting (PONV), and opioid-induced hyperalgesia. Opioid-free anesthesia (OFA), based on multimodal analgesia, offers an alternative to mitigate these issues and enhance recovery in thoracic surgery. However, high-quality evidence confirming its effectiveness and safety is needed.</p> Methods <p>The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed in this study. PubMed, Web of Science, Embase, and Cochrane Library were systematically searched from inception to March 01, 2025, for randomized controlled trials (RCTs) that compared OFA and opioid-based anesthesia (OBA) in patients undergoing video-assisted thoracoscopic surgery (VATS). Study titles, abstracts, and full texts were separately evaluated for eligibility by two researchers; disagreements were resolved by discussion or a third researcher. The Cochrane Risk of Bias tool was used to evaluate the risk of bias in included studies. Primary outcomes included PONV incidence and 24-h postoperative pain scores. Secondary outcomes included chronic pain, intraoperative hemodynamic events, length of stay in the recovery room, length of hospitalization, and quality of recovery (as measured by QoR-40/QoR-15).</p> Results <p>This systematic review and meta-analysis consisted of 10 RCTs involving 1,106 patients. OFA reduced the risk of PONV (risk ratio (RR) = 0.41, 95% confidence interval (CI): 0.380–0.665) and the incidence of postoperative chronic pain at 3 months (RR = 0.566, 95% CI: 0.347–0.925), compared with OBA. However, the 24-h postoperative pain scores did not differ (MD = 0.082, <i>p</i> = 0.305). Bradycardia incidence was lower in the OFA group, but hypotension rates did not differ. The length of stay in recovery rooms and the length of hospitalization did not differ significantly. Although 24-h QoR-40 scores favored OFA (mean difference = 2.914, 95% CI: 1.017–4.811), this improvement did not reach the clinically established threshold of 6.3 points.</p> Conclusion <p>Without worsening intraoperative hemodynamic instability or extending postoperative recovery, OFA significantly reduced the incidence of PONV and chronic pain in patients undergoing VATS. These results validate OFA as a potentially safe and effective anesthetic strategy for improving postoperative recovery after thoracic surgery. Further large-scale RCTs are warranted to standardize OFA protocols and validate its long-term advantages.</p> Trial registration <p>Registration of systematic reviews: CRD42025636410.</p>